Short-chain fatty acids ameliorate experimental anti-glomerular basement membrane disease.

BACKGROUND: Short-chain fatty acids (SCFAs), as the link between gut microbiota and the immune system, had been reported to be protective in many autoimmune diseases by the modulation of T cell differentiation. The pathogenic role of autoreactive Th1 and Th17 cells and the protective role of Treg cells in the pathogenesis of anti-GBM disease have been fully demonstrated. Thus, the present study aimed to investigate the therapeutic effects of SCFAs in a rat model of anti-GBM disease. MATERIALS AND METHODS: Experimental anti-GBM disease was constructed by immunizing Wistar Kyoto rats with a nephrogenic T cell epitope α3127-148, and intervened by sodium acetate, sodium propionate, or sodium butyrate, 150 mM in the drinking water from day 0 to 42. Kidney injury was accessed by the biochemical analyzer, immunofluorescence, and immunohistochemistry. Antibody response was detected by ELISA. T cell clustering and proliferation were detected by flow cytometry. Human kidney 2 (HK2) cells were stimulated in vitro and cytokines were assessed by quantitative real-time PCR. RESULTS: Treatment with sodium acetate, sodium propionate, or sodium butyrate ameliorated the severity of kidney impairment in rats with anti-GBM glomerulonephritis. In the sodium butyrate-treated rats, the urinary protein, serum creatinine, and blood urea nitrogen levels were significantly lower; the percentage of crescent formation in glomeruli was significantly reduced; and the kidneys showed reduced IgG deposition, complement activation, T cell, and macrophage infiltration as well as the level of circulating antibodies against anti-α3(IV)NC1. The treatment of sodium butyrate reduced the α3127-148-specific T cell activation and increased the Treg cells differentiation and the intestinal beneficial bacteria flora. It also alleviated the damage of HK2 cells treated with inflammatory factors and complement. CONCLUSION: Treatment with SCFAs, especially butyrate, alleviated anti-GBM nephritis in rat model, indicating its potential therapeutic effects in clinical usage.

Possible implication of intermolecular epitope spreading in the production of anti-glomerular basement membrane antibody in anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is sometimes complicated by anti-glomerular basement membrane (GBM) disease. Proteases, including elastase, released from neutrophils activated by ANCA are implicated in the pathogenesis of AAV. Epitopes of anti-GBM antibody exist in the α3-subunit non-collagenous (NC1) domain of collagen type IV [Col (IV)]. This region, called α3(IV)NC1, is structurally cryptic. This study aimed to determine the production mechanism of anti-GBM antibody in AAV. METHODS: We first examined whether α3(IV)NC1 could be revealed by the digestion of formalin-fixed, paraffin-embedded (FFPE) normal kidney sections and Col (IV) by proteases, including neutrophil elastase, using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Next, the reveal of α3(IV)NC1 and the infiltration of CD11c+ macrophages in the affected kidneys were evaluated by IHC and immunofluorescent staining using FFPE sections. Finally, the production of anti-GBM antibody in AAV rats was determined by ELISA. RESULTS: α3(IV)NC1 was revealed by the digestion of FFPE normal kidney sections and Col (IV) by proteases. Although the reveal of α3(IV)NC1 was observed in sclerotic glomeruli regardless of causative diseases, CD11c+ macrophages near α3(IV)NC1 were characteristics of AAV. Anti-GBM antibody was produced subsequent to ANCA in some AAV rats. IHC demonstrated the reveal of α3(IV)NC1 in affected renal tissues and the infiltration of CD11c+ macrophages around the sites. CONCLUSIONS: The collective findings suggest that, in AAV, proteases released from neutrophils activated by ANCA digest Col (IV) and result in the reveal of α3(IV)NC1, CD11c+ macrophages present GBM epitopes, and then the host's immune system produce anti-GBM antibody.

SARS-CoV-2 infection and recurrence of anti-glomerular basement disease: a case report.

BACKGROUND: Anti-glomerular basement membrane disease (GBM) disease is a rare autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary haemorrhage. Recently, an association between COVID-19 and anti-glomerular basement membrane (anti-GBM) disease has been proposed. We report on a patient with recurrence of anti-GBM disease after SARS-CoV-2 infection. CASE PRESENTATION: The 31-year-old woman had a past medical history of anti-GBM disease, first diagnosed 11 years ago, and a first relapse 5 years ago. She was admitted with severe dyspnoea, haemoptysis, pulmonary infiltrates and acute on chronic kidney injury. A SARS-CoV-2 PCR was positive with a high cycle threshold. Anti-GBM autoantibodies were undetectable. A kidney biopsy revealed necrotising crescentic glomerulonephritis with linear deposits of IgG, IgM and C3 along the glomerular basement membrane, confirming a recurrence of anti-GBM disease. She was treated with steroids, plasma exchange and two doses of rituximab. Pulmonary disease resolved, but the patient remained dialysis-dependent. We propose that pulmonary involvement of COVID-19 caused exposure of alveolar basement membranes leading to the production of high avidity autoantibodies by long-lived plasma cells, resulting in severe pulmonary renal syndrome. CONCLUSION: Our case supports the assumption of a possible association between COVID-19 and anti-GBM disease.

The clinical and immunological features of the post-extracorporeal shock wave lithotripsy anti-glomerular basement membrane disease.

INTRODUCTION: Extracorporeal shock wave lithotripsy (ESWL) is a noninvasive modality to treat urolithiasis, with complications including tissue damage and hematoma of kidney parenchyma. Anti-glomerular basement membrane (GBM) disease is suggested to be a rare complication of ESWL since it was reported in several cases to occur after ESWL. However, the clinical and immunological features of the ESWL-associated anti-GBM disease have not been fully investigated so far. CASE PRESENTATION: Here, we present the clinical, pathological, and immunological characteristics of three patients with the post-ESWL anti-GBM disease in our hospital. Anti-GBM disease occurred within a median of 22 months after ESWL treatment. It presented with similar clinical features to the classic anti-GBM disease, including fever, gross hematuria, and rapidly progressive glomerulonephritis (RPGN) with poor renal prognosis. Sera from all patients recognized the α3(IV)NC1 in GBM, but with IgG2 and IgG4 as the dominant IgG subclasses. CONCLUSION: Although further exploration is required to prove the causal relationship in this rare condition, our study reminds physicians that patients developing acute renal insufficiency after ESWL should lead to the suspicion of anti-GBM disease and in-time diagnosis and treatment.

Complexities of the glomerular basement membrane.

The glomerular basement membrane (GBM) is a key component of the glomerular capillary wall and is essential for kidney filtration. The major components of the GBM include laminins, type IV collagen, nidogens and heparan sulfate proteoglycans. In addition, the GBM harbours a number of other structural and regulatory components and provides a reservoir for growth factors. New technologies have improved our ability to study the composition and assembly of basement membranes. We now know that the GBM is a complex macromolecular structure that undergoes key transitions during glomerular development. Defects in GBM components are associated with a range of hereditary human diseases such as Alport syndrome, which is caused by defects in the genes COL4A3, COL4A4 and COL4A5, and Pierson syndrome, which is caused by variants in LAMB2. In addition, the GBM is affected by acquired autoimmune disorders and metabolic diseases such as diabetes mellitus. Current treatments for diseases associated with GBM involvement aim to reduce intraglomerular pressure and to treat the underlying cause where possible. As our understanding about the maintenance and turnover of the GBM improves, therapies to replace GBM components or to stimulate GBM repair could translate into new therapies for patients with GBM-associated disease.

Long-term outcomes in kidney transplant recipients with end-stage kidney disease due to anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (GBM) disease causes rapidly progressive glomerulonephritis and end-stage kidney disease (ESKD). Studies of post-transplant outcomes in patients with ESKD due to anti-GBM disease in the United States are lacking. To better characterize outcomes of transplant recipients with a history of anti-GBM disease, we examined patient survival and graft survival among recipients with anti-GBM disease compared with IgA nephropathy at a single center in the United States. We analyzed patient survival, graft survival, disease recurrence, and malignancy rates for kidney transplant recipients with ESKD due to biopsy-proven anti-GBM disease who underwent kidney transplantation at our center between 1994 and 2015. 26 patients with biopsy-proven anti-GBM disease and 314 patients with IgAN underwent kidney transplantation from 1994 to 2015. The incidence of graft loss was 6.2 per 100 person-years for anti-GBM disease, which was similar to IgAN (4.08 per 100 person-years, p = .09). Patient mortality for anti-GBM was 0.03 per 100 person-years, similar to IgAN (0.02 per 100 person-years, p = .12). Disease recurrence occurred in one of the 26 anti-GBM patients. Four out of 26 patients (15%) developed malignancy, most commonly skin cancer. Long-term graft and patient survival for patients with ESKD due to anti-GBM was similar to IgAN after kidney transplantation.

A Case of Recurrent Atypical Anti-Glomerular Basement Membrane Nephritis Suspicion after Renal Transplantation.

Atypical anti-glomerular basement membrane (GBM) nephritis is a rare variant of the classical anti-GBM antibody disease. Patients present with an undetectable anti-GBM antibody but show linear glomerular basement membrane staining for immunoglobulin. We present a 69-year-old man who underwent a living-donor kidney transplant. The aetiology of the renal failure was a focal segmental glomerulonephritis-like lesion resistant to immunosuppressive therapy. A renal graft biopsy revealed diffuse endocapillary hypercellularity, and mild mesangiolysis with linear GBM staining for IgG. The patient was diagnosed with atypical anti-GBM nephritis since the patient tested negative for circulating anti-GBM antibodies. Treatment involved intravenous methylprednisolone, plasma exchange, and rituximab administration. Protocol graft biopsy performed 1 year after the renal transplant showed a focal segmental glomerulonephritis-like lesion possibly progressing from endocapillary hypercellularity and mesangiolysis. These findings were similar to his native kidney biopsy findings. Although classical recurrent anti-GBM nephritis is rare when a renal transplant is performed after decreased disease activity, this case was considered as a case of recurrent atypical anti-GBM nephritis after renal transplant.

Clinical-Pathological Features and Outcome of Atypical Anti-glomerular Basement Membrane Disease in a Large Single Cohort.

Background: Atypical cases of anti-glomerular basement membrane (GBM) disease had absent circulating antibodies but linear IgG deposits along GBM in the kidneys. Herein, we reported the clinical-pathological features and outcome of these rare cases. Methods: Linear IgG deposit along GBM were examined by immunofluorescence on renal specimens, with exclusion of diabetic kidney disease. Circulating anti-GBM antibodies were tested by commercial ELISA assay. Clinical, pathological and follow-up data were retrospectively analyzed. Results: From 2013 to 2018, a total of 60 patients were diagnosed as atypical anti-GBM disease. They had a male predominance, with an average age of 51.7 ± 15.6 years. Three (5.0%) patients had alveolar hemorrhage. Forty five percent of them presented with acute kidney disease. All patients had linear IgG deposit along GBM, some in addition on tubular basement membrane and/or Bowmans' capsules. C3 deposition was found in 65.0% of the patients. 41.7% (25/60) of the patients showed crescent formation and the percentage of crescent was (34.7 ± 23.5)% in those patients. They had higher prevalence of hematuria and C3 deposit, higher levels of serum creatinine, worse renal and patient survival than those without crescent (P < 0.05). During the follow-up of 35.7 ± 21.4 months, 14 (23.3%) patients progressed to ESRD. The serum creatinine on diagnosis [per 200 µmol/L increase, HR (95% CI): 2.663 (1.372, 5.172), P = 0.004], serum C3 [per 0.1 g/L increase, HR (95% CI): 0.689(0.483, 0.984), P = 0.040] and the intensity of kidney C3 staining [per 1+ increase, HR (95% CI): 2.770 (1.115, 6.877), P = 0.028] were independent predictive factors for kidney outcome. Nine (15.0%) patients died of all causes. Conclusions: Atypical anti-GBM disease manifested milder kidney injury and scarce pulmonary hemorrhage compared to the classical cases. Though heterogeneous, a substantial number of the patients had complement activation and crescent formation. Patients having crescents presented with more severe clinical course and worse outcomes. The poor kidney and patient prognosis emphasize prompt interventions from physicians. The immunosuppressive intervention was not associated with kidney or patient outcome. Further studies are needed to address the optimal therapeutic regimen.

Glomerulonephritis With Positive Anti-Glomerular Basement Membrane Antibodies Following Alemtuzumab Treatment.

Presentation A 28 year old female presented to the emergency department with a one week history of headache, vomiting and diaphoresis. Creatinine on admission was 492 and urinalysis revealed blood and protein. This was 5 months after a second infusion of Alemtuzumab, for treatment of highly active relapsing remitting multiple sclerosis. Diagnosis Anti-glomerular basement membrane disease was diagnosed after a vasculitic screen was sent for suspected glomerulonephritis. Treatment Unfortunately despite early diagnosis and immunosuppressive treatment, the patient progressed to end stage kidney failure. Conclusion It is important to maintain a high index of suspicion and test for anti-GBM disease in patients receiving alemtuzumab who develop acute renal failure.

Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from Actinomyces.

BACKGROUND: Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α3127-148 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected. METHODS: To investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity. RESULTS: On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human α3127-148. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat α3127-148. B7 induced T cell activation from human α3127-148-immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7's pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in α3135-145-immunized mice. CONCLUSIONS: Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.

[Review on anti-glomerular basement membrane disease or Goodpasture's syndrome]. / Mise au point sur la maladie des anticorps anti-membrane basale glomérulaire ou syndrome de Goodpasture.

Anti-glomerular basement membrane (anti-GBM) disease or Goodpasture's syndrome is a small vessel vasculitis affecting the capillary beds of kidneys and lungs. It is an autoimmune disease mediated by autoantibodies targeting the glomerular and alveolar basement membranes, leading to pneumorenal syndrome. It is a rare, monophasic and severe disease, associating rapidly progressive glomerulonephritis and alveolar hemorrhage. The presence of antineutrophil cytoplasmic antibodies (ANCA) is reported in 20 to 60% of cases. Management should be prompt and combine plasma exchange with systemic corticosteroids and immunosuppressive therapy by cyclophosphamide. The objective of this review is: 1) to describe the pathogenesis, clinical and histological features of the disease; 2) to characterize double-positive anti-GBM/ANCA patients; 3) to highlight the prognostic factors of renal and global survival, and 4) to focus on the treatment of anti-GBM disease.

Molecular Analysis of Goodpasture's Disease Following Hematopoietic Stem Cell Transplant in a Pediatric Patient, Recalls the Conformeropathy of Wild-Type Anti-GBM Disease.

Background: Goodpasture's disease (GP) is mediated by autoantibodies that bind the glomerular and alveolar basement membrane, causing rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. The autoantibodies bind neoepitopes formed upon disruption of the quaternary structure of α345NC1 hexamer, a critical structural domain of α345 collagen IV scaffolds. Hexamer disruption leads to a conformational changes that transitions α3 and α5NC1 subunits into immunogens, however, the trigger remains unknown. This contrasts with another anti-GBM disease, Alports' post-transplant nephritis (APTN), where the pathogenic alloantibody binds directly to native NC1 hexamer. The current report includes the first study of antigenic specificity and allo-incompatability in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). Results: The anti-GBM antibodies were found to be directed predominantly against the EA epitope of the α3 NC1 monomer of collagen IV and developed rapidly in patient serum reaching peak level within 5 weeks. Autoantibody binding to native α345NC1 hexamer was minimal; however, binding was greatly increased upon dissociation of the native hexamer. There were no polymorphic genetic differences between donor and recipient collagen IV genes which would be predicted to cause a significant NC1 conformational change or to provide a target for antibody binding. Both patient and donor possessed the Goodpasture's susceptibility HLA-allele DRB1*1501. Conclusions: The current report includes the first in-depth study of allo-incompatability and antigenic specificity in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). No polymorphic genetic differences were identified between donor and recipient collagen IV genes which would be predicted to provide a target for antibody binding. Furthermore, autoantibody binding to native α345NC1 hexamer was minimal, increasing greatly upon dissociation of the native hexamer, resembling wild-type GP diseases and marking this as the first example of a post-HSCT conformeropathy.

Recurrence of Goodpasture syndrome without circulating anti-glomerular basement membrane antibodies after kidney transplant, a case report.

BACKGROUND: Goodpasture Syndrome (GS) is an autoimmune disease caused by the development of auto-antibodies against the Glomerular Basement Membrane (GBM). Linear deposit of immunoglobulins G on the GBM detected by immunofluorescence analysis of renal biopsies is a GS pathognomonic finding. GS is commonly monophasic and its incidence is 1.6 case per million per year. CASE PRESENTATION: This report describes and discusses the case of a 40-year-old woman who one year after allograft kidney transplant, presented with acute pulmonary and renal symptoms of GS, leading to acute graft dysfunction, without circulating anti-GBM antibody detection in laboratory assays. She received a living donor kidney transplant 4 years after the first diagnosis of GS without circulating anti-GBM antibodies, when considered in remission. CONCLUSIONS: In both episodes, the diagnosis of GS was based exclusively on the kidney biopsy that showed rapidly progressing glomerulonephritis with deposition of immunoglobulins G on the GBM. Although rare, the management of patients with GS without circulating anti-GBM antibodies is difficult due to the lack of standardized follow-up guidelines to reduce the risk of GS recurrence after kidney transplantation.

Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes.

BACKGROUND: Goodpasture syndrome (GP) is a pulmonary-renal syndrome characterized by autoantibodies directed against the NC1 domains of collagen IV in the glomerular and alveolar basement membranes. Exposure of the cryptic epitope is thought to occur via disruption of sulfilimine crosslinks in the NC1 domain that are formed by peroxidasin-dependent production of hypobromous acid. Peroxidasin, a heme peroxidase, has significant structural overlap with myeloperoxidase (MPO), and MPO-ANCA is present both before and at GP diagnosis in some patients. We determined whether autoantibodies directed against peroxidasin are also detected in GP. METHODS: We used ELISA and competitive binding assays to assess the presence and specificity of autoantibodies in serum from patients with GP and healthy controls. Peroxidasin activity was fluorometrically measured in the presence of partially purified IgG from patients or controls. Clinical disease severity was gauged by Birmingham Vasculitis Activity Score. RESULTS: We detected anti-peroxidasin autoantibodies in the serum of patients with GP before and at clinical presentation. Enriched anti-peroxidasin antibodies inhibited peroxidasin-mediated hypobromous acid production in vitro. The anti-peroxidasin antibodies recognized peroxidasin but not soluble MPO. However, these antibodies did crossreact with MPO coated on the polystyrene plates used for ELISAs. Finally, peroxidasin-specific antibodies were also found in serum from patients with anti-MPO vasculitis and were associated with significantly more active clinical disease. CONCLUSIONS: Anti-peroxidasin antibodies, which would previously have been mischaracterized, are associated with pulmonary-renal syndromes, both before and during active disease, and may be involved in disease activity and pathogenesis in some patients.

[Antiglomerular basement disease in children: Literature review and therapeutic options]. / Syndrome de Goodpasture et maladie des anticorps anti-membrane basale chez l'enfant : revue de la littérature.

Antiglomerular basement membrane glomerulonephritis is a rare autoimmune disease characterized by rapidly progressive glomerulonephritis that may be associated with pulmonary hemorrhage (Goodpasture syndrome). The disease is caused by autoantibodies (classically IgGs) directed against the α3 subunit of type IV collagen. This is a rare disease in the adult population and extremely rare in children, with a reported cumulative annual incidence at 1/106 people/year. Among scarce reported pediatric cases (n=31), most are girls (M/F sex ratio, 1:4), and the mean age at diagnoses is 9.2±4.6 years. A medical diagnosis is an emergency and is based on the identification of specific antibodies in the serum, and pathognomonic linear fixation of IgGs along the glomerular basement membrane. Without appropriate treatment, the disease is generally fulminant, and patient and kidney survival is poor. Indeed, glomerular function strongly correlates with histological lesions. The current guidelines recommend the use of plasma exchanges and immunosuppressive drugs. For the past few years, alternative therapeutics such as specific anti-B-cell antibodies (rituximab) or specific extrarenal cleansing such as immunoadsorption have been successfully used in adults. Immunoadsorptions (IAs) can remove pathogenic IgGs from the circulation and do not require plasma infusions, contrary to plasma exchanges. In this review, we discuss the key points of antiglomerular basement membrane glomerulonephritis diagnosis and conventional or alternative therapeutics.

Spatial and Temporal Clustering of Anti-Glomerular Basement Membrane Disease.

BACKGROUND AND OBJECTIVES: An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties. RESULTS: Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster (n=10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster (n=7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival. CONCLUSIONS: To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.

Myeloid mineralocorticoid receptor activation contributes to progressive kidney disease.

Clinical and experimental studies have shown that mineralocorticoid receptor (MR) antagonists substantially reduce kidney injury. However, the specific cellular targets and mechanisms by which MR antagonists protect against kidney injury must be identified. We used conditional gene deletion of MR signaling in myeloid cells (MR(flox/flox) LysM(Cre) mice; MyMRKO) or podocytes (MR(flox/flox) Pod(Cre) mice; PodMRKO) to establish the role of MR in these cell types in the development of mouse GN. Accelerated anti-glomerular basement membrane GN was examined in groups of mice: MyMRKO, PodMRKO, wild-type (WT) littermates, and WT mice receiving eplerenone (100 mg/kg twice a day; EPL-treated). At day 15 of disease, WT mice had glomerular crescents (37%±5%), severe proteinuria, and a 6-fold increase in serum cystatin-C. MyMRKO, PodMRKO, and EPL-treated mice with GN displayed proteinuria similar to that in these disease controls. However, MyMRKO and EPL-treated groups had a 35% reduction in serum cystatin-C levels and reduced crescent numbers compared with WT mice, whereas PodMRKO mice were not protected. The protection observed in MyMRKO mice appeared to result predominantly from reduced recruitment of macrophages and neutrophils into the inflamed kidney. Suppression of kidney leukocyte accumulation in MyMRKO mice correlated with reductions in gene expression of proinflammatory molecules (TNF-α, inducible nitric oxide synthase, chemokine (C-C motif) ligand 2, matrix metalloproteinase-12), tubular damage, and renal fibrosis and was similar in EPL-treated mice. In conclusion, MR signaling in myeloid cells, but not podocytes, contributes to the progression of renal injury in mouse GN, and myeloid deficiency of MR provides protection similar to eplerenone in this disease.

Neonatal Fc receptor promotes immune complex-mediated glomerular disease.

The neonatal Fc receptor (FcRn) is a major regulator of IgG and albumin homeostasis systemically and in the kidneys. We investigated the role of FcRn in the development of immune complex-mediated glomerular disease in mice. C57Bl/6 mice immunized with the noncollagenous domain of the α3 chain of type IV collagen (α3NC1) developed albuminuria associated with granular capillary loop deposition of exogenous antigen, mouse IgG, C3 and C5b-9, and podocyte injury. High-resolution imaging showed abundant IgG deposition in the expanded glomerular basement membrane, especially in regions corresponding to subepithelial electron dense deposits. FcRn-null and -humanized mice immunized with α3NC1 developed no albuminuria and had lower levels of serum IgG anti-α3NC1 antibodies and reduced glomerular deposition of IgG, antigen, and complement. Our results show that FcRn promotes the formation of subepithelial immune complexes and subsequent glomerular pathology leading to proteinuria, potentially by maintaining higher serum levels of pathogenic IgG antibodies. Therefore, reducing pathogenic IgG levels by pharmacologic inhibition of FcRn may provide a novel approach for the treatment of immune complex-mediated glomerular diseases. As proof of concept, we showed that a peptide inhibiting the interaction between human FcRn and human IgG accelerated the degradation of human IgG anti-α3NC1 autoantibodies injected into FCRN-humanized mice as effectively as genetic ablation of FcRn, thus preventing the glomerular deposition of immune complexes containing human IgG.

Pathogenesis of rapidly progressive glomerulonephritis: what do we learn?

Rapidly progressive glomerulonephritis (RPGN) is a life-threatening disease with a poor prognosis. In this review, the pathogenesis of RPGN owing to antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis and anti-GBM diseases is discussed. By the model of nephrotoxic nephritis, T cells, dendritic cells and toll-like receptors are involved in podocyte activation and parietal epithelial cell proliferation which contribute to the crescent formation and glomerular injury. Furthermore, growth factors and Goodpasture autoantigen are also involved in the onset of the disease. In the study of ANCA-associated glomerulonephritis, the role of lysosome-associated membrane protein (LAMP)-2 and neutrophil extracellular traps is well studied. However, the role of LAMP-2 in the disease pathogenesis remains uncertain. We hope this review can help us to further understand the pathogenesis of the disease.